Process of preparing sex hormones



Patented M... 26, 1946 UNITED I STATES; PATENT OFFICE PROCESS OFPREPARING SEX HORMONES Russell Earl Marker, State College, Pa., andEugene L. Wittle, Detroit, Mir-.11., assignors to No Drawing.

Parke, Davis 8: Company, Detroit, Mieln, a corporation of MichiganApplication October 25, .1940, Serial No. 362,836

27 Claims. (Cl. 260-3973) sex hormones can be prepared from sterols orbile acids in improved yields.

Another object of this invention is to afiord a simplified process forthe preparation of compounds simply convertible into sex hormones.

Yet another object of this invention is to ailord a new process for thepreparation of A -3-keto steroids such as the sex hormones from A-unsaturated steroids.

Other objects will become apparent on perusal of this specification andthe appended claims.

In the. past, steroidal sex hormone intermediates, i. e., compounds ofthe androstane and pregnane series, have been prepared by protecting theC3 hydroxyl and the A double bond of sterols such as cholesterol,cinchol, sitosterol and other sterols, and then oxidatively removing allor the greater portion of the side-chain attached to C11. Because of theinstability and sensitivity of the dihalides of esters of sterols, thisprocess does not give very satisfactory yields. In order to obtain thebest results, the conditions of oxidation must be carefully controlledand even under these conditions it is diflicult to recover a reasonableamount of the unreacted starting material. Onthe other hand, theoxidation of sterol derivatives which are more stable than the dihalidesoi the esters of sterols gives better yields, but now it be.- comes morediillcult to convert the sex hormone intermediates so formed into thesex hormones. themselves. For example, while the oxidation of theacetate of coprostanol proceeds reasonably satisfactorily, thesubsequent conversion of the androstane and pregnane compounds thusobtained into sex hormones requires numerous steps with a very lowoverall yield.

We have set ourselves to the problem of improving the yields in thepreparation of sex hormones iromsterols and bile acids and to this endhave succeeded in developing a process in which the step of oxidationproceeds in good yields to -Our process consists essentially in treatinga steroid 01 the formula,

CH: CH:

where R is a member of the group consisting of hydrocarbon radicals andoxygenated hydrocarbon radicals, X is a halogen, and one of Y and Z is amember of the group consisting of hydrogen and halogen, the other beinghydrogen, with an agent'capable of oxidatively rupturing carbon-tocarbonbonds of the group'R, treating the oxidation products having a shortenedside-chain thus obtained to obtain the corresponding A -unsaturatedsteroids, and treating these with an agent capable of oxidizing amethylene group adjacent to a double bond thus forming the corresponding3-keto zi -unsaturated steroids having a shortened side-chain.

In greater detail, our new process consists first in forming a A*-' or A-unsaturated sterol or bile acid derivative. Because of theiravailability, we prefer to use as starting materials, the naturallyoccurring sterols in which the side-chain R is a hydrocarbon radicalcontaining 8 to 10 carbon atoms. This side'chain may be saturated, as incholesterol CaHrz or sitosterol C1oH21, or it may be unsaturated as .inergosterol CcHr'i. sterols of this type are readily converted into thecorresponding 3-desoxy compounds, i. e. into the A or A -unsaturatedhydrocarbons. may be distilled at atmospheric pressure to give A-cholestene, or it may be treated with phosphorous pentachloride orthionyl chloride to form cholesteryl chloride, and the latter reduced asfor example with sodium and amyl alcohol to yield A -cholestene.

The A4 or A -unsaturated steroidal hydrocarbon used as a startingmaterial is first treated with halogen or hydrohalic acid to add theelements of these substances to the steroidal double bond. We prefer touse chlorine, bromine, hydrogen Thus cholesterol chloride or hydrogenbromide in this step. The

compound thus obtained has a halogen atom attached to C and anotherhalogen atom or hydrogen atom, depending upon whether halogen orhydrohalic acid was added, is attached to the other carbon atom of theoriginal double bond. The dihalide or hydrohalide addition product thusobtained is then oxidized under conditions sufficiently vigorous torupture'carbon-to-carbon bonds. While a variety of a en s may beemployed for this purpose, we prefer to use chromic acid, permanganicacid or their salts and we find it most convenient to conduct theoxidation in acetic acid below 100 C. and preferably at 35- Suitabledehalogenating a ents include sodium iodide, zinc and acetic ac d. metalic ma nesium. and the like. and suitable deh dronaloeenating agents arebasic substances such as 'ovridine. sodium acetate and ot er alkalimetal salts of carboxvlic'acids. and the like.

our new method for the preparation of M-unsaturated 3-keto steroids fromA -unsaturated steroids. This method consists in oxidizing to a ketonegroup a methylene group adjacent to a double bond and this oxidation iseffected by first protecting any hydroxyl groups by convertin these intoderivatives such as acetates,- benzoates, trityl ethers or other groupshydrolyzable to give OH and oxidizing the derivative thus obtained withan agent capable of converting into a ketone group a methylene groupadjacent to a double bond. Such agents include chromic acid andpermanganic acid and their salts, as well as selenium dioxide. Theconditions of reaction depend on the particular oxidizing agentemployed, e. g. we prefer to use chromic acid in acetic acid at -60 C.

The selectivereduction of M-androstenone-l'i may be accomplished with awide variety of reducing agents. Theseinclude catalytic hydrogenationwith a Raney nickel catalyst, andthe If a M-unsaturated steroid has beenused as a starting material or if hvdro en halide. was the agent addedto the unsaturated ste o d (either A or AP). then the roduct formedafter removal of the elements of halo en or hvdrohalic acid. as thecasemaybe. is a M-u'nsaturated compound. If; however. the dihalide of aA -unsaturated steroid was the substa ce oxidized. after removal of theelements of halo en the product obtained is a [i -unsaturat d steroidand it is necessary at some point in the rocess to convert this intoaM-unsaturated steroid. This is-done by adding and then removing theelements of hydrohalic acid.

. This shi ting of the double bond from Alto A in the oxidation productsmay be carried out at any stage after the unreacted starting materialhas been removed from the oxidation products but it-must. of course. bedone before the steroid is a ain oxidized to form the 3-keto steroid asdouble bond in the A-' -position. may be converted into thecorresponding A -androstenone-l7.

The M-androstenone-IT thus obtained may be oxidized according to our newmethod to form A -androstendione-3J7 and the latter selectively reducedto form Ai-androstenol-1'7-one-3 (testosterone).

Otherwise the M-androstenone-i'l mav first be selectively reduced underconditions which leave a doublebond unaltered so as to form A-androstenol-l7, the hydroxyl group of the latter rotected bv conversioninto a derivative hydrolyzable to regenerate A -androstenol-17 and thisderivative oxidized according to our new method to form thecorresponding derivative 0! a a dr0steno1-1'7-one-3.

combination of an alkali or alkaline earth metal or aluminum andasubstance having reactive hydrogen atoms. Reducing agents of the latterclass include such combinations as sodium and ethyl alcohol, aluminumamalgam and aqueous ammonium chloride, calciumand methanol, and thelike. Instead of these the reduction may be conducted according to themethod or Meerwe'in and Ponndorfi. using, for example, ammoniumisopropylate and isopropyl alcohol.

It will be appreciated that our invention also comprehends a new groupof intermediates for the preparation of sex hormones. This new group ofsubstances is representable by the generalformula CH1 CH3 where Q is amember of the class consisting of (=0) groups hydrolyzable to =0),

and groups hydrolyzable to This group of substances includesN-androstenone-17, its semicarbazone, its oxime, A -androstenol-l"! andits esters such as its benzoate, acetate, furoate and butyrate.

Our invention may be more fully illustrated by the following examples:

Example 1 (a) In a 12 liter flask is placed 230 g. of A cholestenedibromide prepared, e. g., according to Mauthner, Monatsch. 27, 421(1906), and 500cc. of carbon tetrachloride. When solution is complete, 8liters of glacial acetic acid are added and the solution warmed to 45 C.with stirring. To this stirred solution at 48-50 C. is added dropwise astirred solution of 320 g. of chromic anhydride in 350 cc. of water and800 cc. ofacetic acid over a period of four or live hours. .The solutionIn either case the process involves the use of is stirred at 50 C. forsix hours longer and, then cooled with cold water or ice to 30 C. Thenethyl alcohol (250 cc.) is added slowly to this stirred solution over aperiod of about one-hall hour to destroy any excess chromic anhydride.The acetic acid is then removed under reduced pressure until the volumeof the solution has been reduced about one-half. During the evaporationthe temperature of the solution is kept at.40-45 C. The so- .lution iscooled slightly and the unchanged dibromide filtered oii and dried. Thefiltrate is further concentrated under reduced pressure at 40 C. untilonly a small quantity of acetic acid remains. This residue is dilutedwith 4 liters of water and 2.5 liters of ether'and stirred until all thematerial is in solution. The water layer is separated and extracted with2.5 liters of ether. The combined ethereal extracts are washed well with2 liters of water, 3 liters of water containing 300 cc. of conc.hydrochloric acid, and then twice with 1.5 liters of salt water,sumcient salt being added to cause rapid separation of the layers. Theethereal solution then is evaporated to dryness. the last ether beingtaken oil cautiously to avoid undue heat. The residue contains the di--bromides of A -androstenone-l7, A -pregnenone- 20, and A -cholenicacid.

Instead of using A -cholestene dibromide in the above step, A-cholestene dichloride, n -sitostene dibromide, A -sitostene dichloride,or other dihalides of A -unsaturated hydrocarbons derived from sterolsmay be used instead.

(b) One liter of acetic acid and 5 g. of zinc dust is added to thisresidue and the solution stirred vigorously and heated to .95 C. on thesteam bath. A further 45 g. of zinc dust is added to this stirredsolution in small ortions over a period of forty-five minutes. Then thesolution is filtered from the caked zinc and the latter washed well withacetic acid. The acetic acid filtrate is evaporated to dryness in vacuoon the steam bath and the residue dissolved in 2 liters of ether. Theethereal solution is washed twice with water and the acid fraction isextracted with 5% sodium hydroxide solution until all acids are removed.

(0) The ethereal solution is evaporated to dryness and the residue steamdistilled to remove the volatile products. The' residue is dissolved inether and the water layer removed. After evaporating the ether, theresidue is dissolved in 200 cc. of 95% ethyl alcohol. Five grams ofsemicarbazide hydrochloride and 6 g. of sodium acetate are added and themixture refluxed on the steam bath for four hours, the alcohol beingallowed to" evaporate to one half volume. The solution is cooled anddiluted with 500 cc. of ether. After shaking the suspension for aboutone-half hour with cooling, 200 cc. of water is added. The solution isshaken and cooled in a salt-ice bath and then filtered with suction. Thewhite solid is washed well with water and ether. Then it is refluxedwith 50 cc. of alcohol for one hour, cooled, flltered, and air dried;yield 5 g. of white powdered semicarbazone, M. P. 285-287 C. This is thesemicarbazone oi. A -androstenone-17.

(d) A solution of 6.7 g. of M-androstenone-fl semicarbazone, in 500 cc.of 95% ethyl alcohol, 35 cc. of concentrated sulphuric acid and.35 cc.of water is refluxed for two and one-half hours on the steam bath. Thesolution is diluted with water and the organic material extracted withether. The ethereal solution is washed well with water and sodiumbicarbonate solution and evaporated to dryness. The residue is purifiedby distillation at 80 C. in a molecular still and crystallization fromdilute alcohol to yield a c. or A -androstenone-17, M. P. 100-105 C. Onfurther purification the M. P. may be raised to 105-107" C.

(e) To a solution of 1.7 g. of M-androstenone- 17 in 26 cc. of refluxingn-propyl alcohol is added 2.5 g. of sodium in small portions over aperiod of a half hour. Then the solution is poured into water and thewhite solid collected. This is crystalized from methanol to yield 1.4 g.of A -androstenol-l'l, M. P. 163-165 C.

Three grams of A -androstenol-17 is refluxed for one hour with 30 cc.acetic anhydride and then the solution is evaporated'to dryness underreduced pressure. The residue is dissolved in hot methanol and allowedto crystallize, The A -androstenoi-lT-acetate thus formed has M. P.133-135 C. Hydrolysis of this acetate, e. g., with alcoholic potassiumhydroxide, regenerates the original hydroxy compound, A -androstenol-17.

(j) A stream of dry hydrogen chloride is bubbled for several hoursthrough a-solution of 1 g. of M-androstenol-l'? in about 20 cc. ofchloroform. cooled to 0 C. After the cold solution has stood for severalhours, it is carefully evaporated to dryness under reduced pressure on awater bath. The white solid hydrochloride remaining behind is dissolvedin ethyl alcohol and refluxed for six- -A mixture of these two acetatesgives a depression in melting point to 72-82 C.

A solution of 500 mg. ofn -androstenol-l7 acetate. M. P. 97-100" C. in25 cc. of methanol is refluxed for a half hour with a solution of 1 g.of

potassium hydroxide in 10 cc. of 50% methanol. The solution is dilutedwith water and extracted with ether. The ethereal solution is washedwith water and evaporated to dryness. The A -androstenol-17 is purifiedby crystallization from methanol, and then has M. P. l46-l49 C.

To a solution of 200 mg. of A -androstenol-17 in 100 cc. of acetic acidis added 0.73 cc. of 1.05 molar bromine in acetic acid. After afew'minutes, a solution of 300 mg. of chromic anhydride in 20 cc. of 90%acetic acid is added with shaking. The solution is allowed to stand atroom temperature for one hour and then warmed with five grams of zincdust on the steam bath. The solution is filtered, poured into water andthe product extracted with ether. The ethereal solution is washed wellwith water and dilute'alkali and evaporated to dryness. The residue isdistilled in a molecular still under reduced pressure and thencrystallized from dilute methanol to give M-androstenone-17 of M. P.78-80 C. This ketone gives a depression in melting point to 60-65 C.when mixed with A -androstenone-17.

(y) To a solution of 2 g. of A -androstenol-17 acetate in cc. of glacialacetic at 50 C. is added a solution of 2 g. of chromic anhydridein 25cc. of acetic acid over a period of one hour. The solution ispoured intowater and extracted with ether. The ethereal solution is washed wellwith water and dilute sodium carbonate solution and then evaporated todryness. The resulting oil, which shows a high androgenic activity, istreated in the known manner with Girards reagent I to separate theketonic fraction. The

- crude ketone is hydrolyzed by warming with alcoholic hydrochloric acidand then distilled in a molecular still at 0.01 mm. pressure.Crystallization. of the product so obtained from ether-pens tens ordilute methanol gives testosterone, M P.

1 148-.150 0., identical with the natural product.

' Example 2 (a) A -Androstenol-1'l is prepared, e. g.. as dey scribed inExample 1 (f) (b) To a solution of 2.5 g. of M-androstenoll'l in 200cc.-of acetic acid is added at -45 C. and

with stirring, a solution of 3g. of chromic anhydride in 5000. of 90%acetic acid. The addition requires one-half hour and the solution isthenkept at C. for another half hour. The solution is poured into waterand extracted with ether.

The ethereal layer is washed well with sodium carbonate solution andwater and concentrated to a small volume. 'On cooling this solution forsome time crystals form and are 001..

and dissolved in cc, of acetic lution. at 45 C., thereis added asolution 011.5 g. V

of chromic anhydride in 20 cc. of 90% acetic acid [over a period of ahalf hour. The'mixture is small volume, and rendered cloudy by theaddition of ligroin. On standing, crystals of A -androstenedione-3,17separate. After recrystallization, this product melts at 170. The motherliquor from the separation of the M-androstenelected. They may berecrystallized from ether to yield A -androstenedione-3, 17, M. P,,168-1'70 C.,

identical with the known substance.

Example 3 Y acid are stirred and maintained at 50 C. while a solution of150 g. of calcium permanganate in 600 cc. of water, 100 cc, of sulfuricacid, and 2 l. of

acetic acid is added over a period of four hours. The mixture is stirredfour hours more at 50 0..

dione-3,17'is made slightly turbid with ligroin' and filtered. through acolumn of alumina. The filtrate is evaporated and yields, aftercrystallize tion from dilute acetone, progesterone of M. P. 122 C.

Example 4 (a) M-Cholestene is prepared by the method of Heilbron andSexton, J. Chem. Soc.

and then sulfurdioxide passed into the solution by filtration. Thefiltrate, consisting of an ethereal and an aqueous phase, is set asidefor later treatment as described under ((1) below.

(c) The sparingly soluble sodium salt is suspended in water, and thesuspension acidified strongly. Thismixture is well extracted with etherand the latter washed and'evaporated. The residue is crystallized fromslightly diluted acetic acid and thus yields A -cholenic acid of M, P.160 C. i

(d) The ethereal layer in the filtrate is separated and washed well withsodium hydroxide solution and water. After removing the ether on a steambath, the residue is heated with 200 cc. of acetone, some methanoladded, and the mixture chilled. The crude n -cholestene which separatesis collected and recrystallized. The combined l a fraction collected at7o-110 c. This is fractionally crystallized from dilute methanol andthus yields. M-androstenone-l'l of M, P. '78 80 C.

(e) The combined mother liquors from the above described crystallizationof M-androstenone-17 contains M-androstenone-l'? and A pregnenone-ZO,and are evaporated to dryness (b). To 100 g. of A -cholestene in 500cc..oi

carbon tetrachloride is added a 30% solution of.

bromine in carbon tetrachloride until the double bondis saturated withbromine. Then the mixture is warmed to 50C., 2 1. of acetic acid add ed,and a solution of 100 g. of chromic anhydride in 1 liter of acetic acidat 50 C, over a period of four hours. After stirring for four hours moreat-this temperature, 150 g. of zinc dust is added, in small portions,and the mixture allowed to standovernight. the solution is decanted fromthe sludge, and concentrated in vacuo. The residue is dissolved inwaterand ether, the layers separated, and the ethereal layer washed withsodium hydroxide solution. The ethereal extract is then evaporated todryness, and the ketones removed from the residue in the known manner asthe semi-carbazones. After hydrolysis of the purified semicarbazone, A-androstenone-1'7 of M. P. 79 C.- is obtained.

(c) To 1.5 g. of n -androstenone-l'l in cc. of acetic acid at 40 C.there is added slowly over a period of an hour, a solution of 1.5 g. ofpotassium permanganate in 20 cc. of water and 50 cc. of acetic acid.After standing for an additional hour, the mixture is saturated withsulfur dioxide, concentrated to a smallvolume, and diluted with water.This mixture is extracted with ether and the ethereal layer washed withalkali and water and evaporatedto dryness. The residue yields, aftercrystallization from ether-pen,- tane, A andrdstenedione-Sd'? of M. P.168-'l0 C.

7 Example 5 (a) A -Pregnenone-20, M. P. -C., may be isolated from themother liquors of the preparation of A -androstenone-1'7 as in Example3, (d),or it may be prepared from M-pregnenol- 3(5) -one-20 by the stepsof treatment with phosphorus pentachloride to obtain A-3-chloropregnenone-20, treating this with sodium and amyl alcohol toobtain A -pregnenol-20(a), and treating this as in Example 1, to obtainM-preg'nev none-20.

(b) To a solution of 2 g. of A -pregnenone-20 in 30 cc. of acetic acidat 45 C. is added over acid. 'rotmwi distillin cholesterol atatmospheric pressure according to The next day The residual sirup isdissolved in ether, shaken out with sodium hydroxide and water, and theethereal extract evaporated. The residue is sublimed in a high vacuumand then crystallized from dilute acetone and thus gives progesteronemelting at 120 C.

The above examples are intended to illustrate but not to limit the scopeor our invention. Other modes oi employing our process apparent to thoseskilled in the art after this disclosure, are intended to fall withinthe scope of our invention and accordingly we wish to limit the scope ofour invention only as indicated in the ap nded claims.

What we claim as or invention is:

1. The process which comprises treating a steroid of the formula,

CH: CH;

where R is a memberof the group consisting of hydrocarbon radicals andoxygenated hydrocarbon radicals, X is a. halogen, and one or Y and Z isa member or the group consisting of hydrogen and halogen, the otherbeing hydrogen, with an agent capable of oxidatively rupturingcarbon-to-carbon bonds, treating the oxidation products having ashortened side-chain thus obtained to obtain the correspondingM-unsaturated steroids, said treatment being determined by the nature ofY and Z, so that when Y is-halogen and Z is hydrogen, the treatmentcomprises the step of reacting the oxidation products with adehalogenating agent, when Y and Z are both hydrogen the treatmentcomprises the step of reacting the oxidation products with adehydrohalogenating agent, and when Y is hydrogen and CH: CH:

where R represents a sterol-side chain contain- 1 18 8 to carbon atoms,and X is selected from the class consisting of chlorine and bromide withan oxidizing agent selected from the class consisting of chromic acid,permanganic acid, and

their salts, treating the oxidation products thus obtained with adehalogenating agent, isolating the A -androsten0ne-17 thusformed-converting pounds of hexavalent chromium, compounds ofheptav-alent manganese, and selenium dioxide, and separating the3-keto-A -androstenol- 1! compound thus produced.

3. The process which comprises treating a steroid of the formula,

CH: CH:

I where R represents a sterol-side chain containing 8 to 10 carbonatoms, and X is selected from the class consisting of chlorine andbromine with an oxidizing agent selected from the class consisting ofchromic acid, permanganic acid, and their salts, treating the oxidationproducts thus obtained with a dehalogenating agent, isolating the A-androstenone-l'? thus formed, reducing to a carbinol group the ketonegroup of said A*- androstenone-17 under conditions which leave doublebonds unaltered, protecting the C11 hydroxyl group by conversioninto aderivative hydrolyzable to regenerate the Cr: hydroxyl group, treatingsaid derivative of M-androstenol-l'l with an oxidizing agent capable ofoxidizing to a ketone group a methylene group adjacent to a double bond,said oxidizing agent being selected from the group consisting ofcompounds of hexavalent chromium, compounds of heptavalent manganese,and selenium dioxide, and separating the 3-keto- A -androstenol-17compound thus produced.

4. The process which comprises treating a steroid of the formula, I

where It represents asterol-side chain containing 8 to 10 carbon atoms,and X is selected from the class consisting-of chlorine and bromine withan oxidizing agent selected irom the class consisting of chromic acid,permanganic acid, and their salts, treating the oxidation products thusobtained with a dehydrohalogenating agent, isolating the A-androstenone-ll thus formed, reducing to a carbinol group the ketonegroup of said A-androstenone-l7 under conditions which leave doublebondsunaltered, protectingthe 011 by droxyl group by conversion into aderivative 1W- drolyzable to regenerate the C11 hydroxyl group.

treating said derivative of A -androstenol-1'1 with an oxidizing agentcapable of oxidizing to a ketone group a methylene 'group adjacent to adouble bond, said oxidizing agent being selected from the groupconsisting of compounds of hexavalent chromium, compounds of heptavalentmanganese, and selenium dioxide, and separating the 3-keto-A-androstenol-17 compound thus produced.

5. The process which comprises treating a steroid of the formula,

CH: CH:

, the C11 hydroxyl group by conversion into a derivative hydrolyzable toregenerate the Cr: hydroxyl group, treating said derivative of n-androstenol- 17 with an oxidizing agent capable of oxidizing to aketone group a methylene group adjacent to a double bond, said oxidizingagent being selected from the group consisting 01 compounds ofhexavalent chromium, compounds 01' heptavalent manganese, and seleniumdioxide, and separating the 3-keto-A -androstenol-1'I compound'thusproduced.

6. The process which comprises treating 5,6-

.dibromocholestane with an excess of chromic acid in acetic acid at35-60 0., treating the oxidation products thus obtained with zinc dust,isolating the M-androstenone-l'l thus formed, reducing to a carbinolgroup the ketone group of said A -androstenone-17 with a reducing agentI selected from the class consisting of, (a) metals more electropositivethan zinc in combination with a substance having reactive hydrogenatoms, (b) molecular hydrogen and a nickel catalyst, and thecombinationof an aluminum' alcoholate and a secondary alcohol,converting the 'A -androstenol-17 thus formed into A -androstenol-17 byaddition and subsequent removal of an agent selected from classconsisting of hydrogen chloride and hydrogen bromide, acylating the C11hydroxyl group to form 17-acyloxy-A -androstene, treating said17-acylqxy-A -androstene with chromic acid in acetic acid at30-60" C.and separating the 17-acyloxy-M-androstenone-ii thus produced. 4

7. The process which comprises treating 5- chloro cholestane with anexcess of chromic acid in acetic acid at 35-60 C., treating theoxidation products thus obtained with an valkali metal salt of anorganic acid, isolating the A -androstenone-l7 thus formed, reducing toa carbinol group the ketone group of said A -androstenone- 17 with areducing agent selected from the class consisting of, (a) metals moreelectropositive than zinc in combination with a substance havingreactive hydrogen'atoms, (b) molecular hydrogen and a nickelcatalyst,-and (0) the combination of an aluminum alcoholate and asecondary alcohol, acylating the C11 hydroxyl group'of the A-androstenol-l7 thus formed, treating said l7-acyloxy-A -androstene withchromic acid in acetic acid at -60 C. and separating the 17- acyloxy-A-androstenone-3 thus produced,

8. The step which comprises reducing A -androstenone-l'l with a reagentselected from the class consisting 0!, (a) metals more electropositivethan zinc in combination with a substance having reactive hydrogenatoms, (b) molecular hydrogen and a nickel catalyst, and (c) thecombination of an aluminum alcoholate anda secondary alcohol, to formM-androstenol-l'l.

9. The step which comprises treating an ester of M-androstenol-l'? withchromic acid in acetic acid at 30-60 0., thus forming an ester 01' Aandrostenol-l7-one-3.

10. A -Androstenol-l7-acetate of melting oint approximately 97-100 C.

11. An ester of the formula CH: CH:

where R is the acyl radical of a lower aliphatic carboxylic acid.

12. The processwhich comprises subjecting a steroidoftheformula,

CH; CH3

where R is a sterol-side chain'containing 8 to 10 carbon atoms and X isselected from the class consisting of chlorine and bromine, to oxidativeside chain degradation by treatment with an oxidizing agent selectedfrom the class consisting of chromic acid, permanganic acid, and theirsalts, treating the oxidation products thus obtained with adehalogenating agent, converting the A unsaturated ketonic steroids thusobtained into the corresponding M-unsaturated steroids by additionthereto and subsequent removal therefrom of hydrohalic acid, andoxidizing said Af-unsaturated steroids with an oxidizing agent capableof oxidizing to a ketone group a methylene group adjacent to a doublebond, said oxidizing agent being selected from the group consisting ofcompounds of hexavalent chromium, compounds of heptavalent manganese andselenium dioxide, thereby obtaining at least one member of the classconsisting of A-androstenedione-3,17. and A -pregnenedione-3,20. v

13. The process which comprises subjecting a steroid of the formula,

CH3 CH7;

where R" is a sterol-side chain containing 8 to 10 carbon atoms and X isselected from the class consisting of chlorine and bromine to oxidativeside chain degradation by treatment; with anoxidizing agent selectedfrom the class consisting f chromic acid, permanganic acid, and theirsalts, treating the oxidation products thus obtained with adehalogenating agent, and oxidizing the resulting M-unsaturated ketonicsteroids with an oxidizing agent capable of oxidizing to a ketone groupa methylene group adjacent to a double bond, said oxidizing agent beingselected from the group consisting of compounds of hexavalent chromium,compounds offheptavalent manganese, and selenium dioxide, therebyobtaining at least one member of the class'consisting ofM-androstenedione-SA'? and A -pregnenedime-3,20. I

14. The process which comprises subjecting a stearoid oi the formula,

16. The process which comprises oxidizing 5- chlorocholestane with anexcess of chromic acid in acetic acid at 35-60 C., dehydrohalogenatingthe ketonic steroids thus obtained with an alkali metal salt of anorganic acid, and oxidizing the resulting (i -unsaturated ketonicsteroids with chromic .acid in acetic acid at 30-60 0., therebyobtaining at least one member of the class consisting of A-androstenedione-3J'7 and A-pregnenedi0ne-3,20.

1'7. A -Androstene-17-ol acylates.

18. M-Androstene-l'l-ol.

19. A process of the character described which comprises treating anandrostane-l'I-one, contaming only a double bond in the rings A and B,with an agent capable of transforming the group --C0- into the groupCII(OH)-, then with an esterifying ageniaand then causing the productthus obtained to react with an oxidizing agent capable of introducing aketo group into the a-position of double bonds.

20. The dimethyl cyclopentanopoly-hydrophenanthrene compounds containingin the 1'!- position an oxo-group and in the rings A and B only a carbondouble bond.

21. The dlmethyl cyclopentanopolyhydrophenanthrene compounds containingin the l'l-position an oxo-group and in the rings A and- B only a carbondouble bond in 4:5-position.

22. The A -androstene-1'7-one oi the formula:

23. The step which comprises treating a steroid ottheformula a on: on,

Q (\J \J dizing to a ketone group a methylene group adjacent to a doublebond, said oxidizing agent being selected from the group consisting ofcompounds of hexavalent chromium, compounds of heptavalent manganese,and selenium dioxide, thereby obtaining at least one member of the classconsisting of A -androstenedione-3,17, and A -pregnenedione-3,20. 15.The process which comprises oxidizing 5,6

dibromocholestane with an excess of chromic acid in acetic acid at 35-60C., dehalogenating with zinc dust the oxidation'products thus obtained,converting the resulting M-unsaturated ketonic steroids to thecorresponding n -unsaturated steroids by addition thereto and subsequentremoval therefrom of an agent selected from the class consisting ofhydrogen chloride and hydrogen bromide, and oxidizing said ,A-unsaturated steroids with chromic acid in acetic acid at 30-60 0.,thereby obtaining at least one member of the class consisting ofM-androstenedione- 3,37 and A*-pregnenedione-3,20.

where Q is a member of the class consisting of and i O-acyl with anoxidizing agent capable of oxidizing to a ketone group a methylene groupadjacent to a double bond, said oxidizing agent being selected from thegroup consisting of compounds of I of the formula on, on;

' dioxide, thus forming A*-androstenedione-3,17.

where Q is a member of the class consisting of (=0), v

- on 0-adyl and 'androstenone-1'I with chromic acid in acetic acid at30-60" 0., thus forming M-androstenedione- 3,17;

27. A compound of the forgnula CH: CH;

where Q is a member of the class consisting of (=0),

. and

RUSSELL EARL MARKER. EUGENE L. WITI'LE.

